Karakterizacija prijenosa alfa-sinukleina u probavnom sustavu

master's thesis

• Title (croatian): Characterization of alpha-synuclein transport in the digestive system
• Author: Pavel Marković
• Mentor: Jan Homolak (mentor)
• Committee member: Ana Babić Perhoč (predsjednik povjerenstva)
• Committee member: Ivana Vuković Brinar (član povjerenstva)
• Committee member: Jan Homolak (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Internal Medicine); Zagreb
• Defense date and country: 2024-09-11, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Basic Medical Sciences; Pharmacology

Abstract

Sve više dokaza upućuje na probavni sustav kao važan etiopatogenetski čimbenik u Parkinsonovoj bolesti (PB). Simptomi vezani uz probavni sustav prevalentni su i javljaju se u prodromalnom stadiju bolesti, a patološki agregati alfa sinukleina (ɑS) u enteričkom živčanom sustavu (EŽS) opisani su prije nakupljanja u mozgu. Bakterijski i prehrambeni sinukleini mogli bi biti važan pokretač agregacije ɑS-a u EŽS-u, međutim, u ovom trenutku apsorpcija i translokacija luminalnog ɑS-a još uvijek nije istražena. Cilj ovog diplomskog rada bio je postaviti i validirati ex vivo model translokacije luminalnog ɑS-a kroz probavnu sluznicu miša i štakora te ispitati mehanizme translokacije. Istraživanja provedena u okviru ovog diplomskog rada pokazala su da ex vivo inkubacija fluorescentno obilježenog αS-a s probavnom sluznicom može poslužiti kao vrijedan model za proučavanje patofizioloških mehanizama povezanih sa sinukleinopatijama. Nakon luminalnog izlaganja, egzogeni αS u najvećoj mjeri nalazi se u epitelnim stanicama (uključujući i epitelne stanice odljuštene u lumen). Nakon toga, luminalni αS nakuplja se stanicama koje izražavaju biljege enteroendokrinih stanica i živčanih stanica, a najvažniji originalni doprinos ovog diplomskog rada je nakupljanje αS-a u enteroglijalnim stanicama što do ovog trenutka nije opisano u literaturi. Radni model postavljen na temelju provedenog istraživanja pretpostavlja translokaciju luminalnog αS kroz stanice probavnog epitela nakon čega dolazi do nakupljanja u nastavcima živčanih i enteroglijalnih stanica koje bi mogle biti ključni posrednici u prijenosu do spletova EŽS-a. Razumijevanje prijenosa αS-a u probavnom sustavu moglo bi doprinijeti razvoju novih ciljanih terapija koje bi mogle spriječiti nastanak i usporiti napredovanje PB-a.

Abstract (english)

There is increasing evidence pointing to the digestive system as a key etiopathogenetic factor in Parkinson's disease (PD). Gastrointestinal symptoms are prevalent and occur during the prodromal stage of the disease, and pathological aggregates of alpha-synuclein (ɑS) in the enteric nervous system (ENS) have been observed before their accumulation in the brain. Bacterial and dietary synucleins could be important triggers for ɑS aggregation in the ENS; however, the absorption and translocation of luminal ɑS have not yet been thoroughly investigated. The aim of this thesis was to establish and validate an ex vivo model of luminal ɑS translocation through the digestive mucosa of mice and rats, and to examine the mechanisms of this translocation. The studies conducted as part of this thesis demonstrated that ex vivo incubation of fluorescently labeled αS with the digestive mucosa can serve as a valuable model for studying pathophysiological mechanisms related to synucleinopathies. Following luminal exposure, exogenous αS was predominantly found in epithelial cells (including epithelial cells shed into the lumen). Subsequently, luminal αS accumulates in cells expressing markers of enteroendocrine and neuronal cells. The most significant original contribution of this thesis is the accumulation of αS in enteroglial cells, a finding that has not been previously described in the literature. The working model proposed based on this research suggests the translocation of luminal αS through digestive epithelial cells, followed by accumulation in the extensions of neuronal and enteroglial cells, which could be key mediators in the transfer to ENS networks. Understanding the translocation of αS in the digestive system could contribute to the development of novel targeted therapies that may prevent the onset and slow the progression of PD.

• Keywords: Alfa-sinuklein; Parkinsonova bolest; Gartrointestinalni trakt; ex vivo model
• Keywords (english): Alpha-synuclein; Parkinson disease; Gastrointestinal tract; Ex vivo model
• Language: croatian
• URN:NBN: urn:nbn:hr:105:176713
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-09-09 22:43:20